Project Summary A central goal of neuroscience research is to advance our understanding of the cellular physiology underlying learning and memory processes. The most extensively studied model for how associative learning is achieved at the cellular level is the Hebbian modification of synapses. However, computational modeling studies have demonstrated that these forms of plasticity follow positive feedback rules, making them inherently destabilizing in nature. Without additional features, Hebbian plasticity could give way to ?unconstrained? changes in synaptic strengths, resulting in the disruption of associative learning. Homeostatic synaptic plasticity is hypothesized to be the basis for neural-network stability during learning-driven changes of synaptic strength. Synaptic scaling, the most extensively studied form of homeostatic synaptic plasticity, functions as a negative-feedback mechanism, bidirectionally regulating synaptic strengths, in a cell- autonomous manner, to maintain an activity set point. Synaptic scaling is thus hypothesized to constrain the positive feedback nature of Hebbian mechanisms while simultaneously preserving circuit features permissive to learning. Despite its potential to impact our current understanding of associative learning processes, this hypothesis remains untested and the consequences of disrupted synaptic scaling on learning remain unknown. This proposal aims to determine the role of homeostatic synaptic scaling in associative learning and memory using a conditioned taste aversion (CTA) paradigm in rats. First, I will confirm that I can induce and block synaptic scaling in gustatory cortex using in-vivo chronic TTX infusions and ex-vivo acute slice electrophysiology. Second, I aim to characterize the effects of synaptic scaling loss on engram excitability. I will train rats on a CTA behavior paradigm and then perform immunofluorescent staining to characterize the time course of learning-driven changes in CTA engram neuron excitability. Then, I will use a combination of ex-vivo acute slice electrophysiology and virus mediated targeting of CTA engram neurons to characterize the impact of blocked homeostatic plasticity on the underlying cellular physiology of associative learning. Lastly, I will determine the role of homeostatic plasticity in memory acquisition & extinction using behavioral training and ex-vivo recordings of CTA engram cells. These experiments will elucidate the behavioral consequences of loss of homeostatic plasticity. Moreover, this research proposal will advance our current understanding of the associative learning and memory mechanisms underlying behavior.